tbuckley/cabot-search huggingface dataset:
Emergent variant modeling of the serological repertoire to norovirus in young children
Authors: Lisa C. Lindesmith, Paul D. Brewer-Jensen, Helen Conrad, Kathleen M. O’Reilly, Michael L. Mallory, Daniel Kelly, Rachel Williams, W. John Edmunds, David J. Allen, Judith Breuer, Ralph S. Baric
Journal: Cell Reports Medicine (2023)

Human norovirus is the leading cause of acute gastroenteritis. Young children and the elderly bear the greatest burden of disease, representing more than 200,000 deaths annually. Infection prevalence peaks at younger than 2 years and is driven by novel GII.4 variants that emerge and spread globally. Using a surrogate neutralization assay, we characterize the evolution of the serological neutralizing antibody (nAb) landscape in young children as they transition between sequential GII.4 pandemic variants. Following upsurge of the replacement variant, antigenic cartography illustrates remodeling of the nAb landscape to the new variant accompanied by improved nAb titer. However, nAb relative avidity remains focused on the preceding variant. These data support immune imprinting as a mechanism of immune evasion and GII.4 virus persistence across a population. Understanding the complexities of immunity to rapidly evolving and co-circulating viral variants, like those of norovirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), and dengue viruses, will fundamentally inform vaccine design for emerging pathogens.
Better understanding of ICI-induced cholangitis for better management
Authors: Lucy Meunier, Alexandre Maria
Journal: Journal for ImmunoTherapy of Cancer (2023)

We read with interest the recent report about histology in liver injury induced by immune checkpoint inhibitors (ICIs) published by Coukos et al .[1][1] In this study, the authors compared the histological lesions of ICI-induced hepatitis (n=27) with those of autoimmune hepatitis (n=11) or primary
Response to a letter to the editor: a better understanding of Immune Checkpoint Inhibitor-induced cholangitis for better management
Authors: Alexander Coukos, Julien Vionnet, Christine Sempoux, Montserrat Fraga
Journal: Journal for ImmunoTherapy of Cancer (2023)

We have the pleasure to further the conversation around checkpoint inhibitor-induced liver injuries or, as Hountondji et al have elegantly coined them, CHILI.[1][1] We would first like to thank Meunier and Maria for their interesting letter in response to our publication.[2][2] They refer, namely,
Role of peripheral blood MRD and 18F-FDG PET in the post-CAR relapse setting: a case study of discordant peripheral blood and bone marrow MRD
Authors: Liora Schultz, Kara Lynn Davis, Ann Walkush, Christina Baggott, Courtney Erickson, Sneha Ramakrishna, Catherine Aftandilian, Norman Lacayo, Helen Ruth Nadel, Jean Oak, Crystal L Mackall
Journal: Journal for ImmunoTherapy of Cancer (2023)

Chimeric antigen receptor (CAR) T cell therapy is an effective salvage therapy for pediatric relapsed B-cell acute lymphoblastic leukemia (B-ALL), yet is challenged by high rates of post-CAR relapse. Literature describing specific relapse patterns and extramedullary (EM) sites of involvement in the post-CAR setting remains limited, and a clinical standard for post-CAR disease surveillance has yet to be established. We highlight the importance of integrating peripheral blood minimal residual disease (MRD) testing and radiologic imaging into surveillance strategies, to effectively characterize and capture post-CAR relapse. Main body: Here, we describe the case of a child with multiply relapsed B-ALL who relapsed in the post-CAR setting with gross non-contiguous medullary and EM disease. Interestingly, her relapse was identified first from peripheral blood flow cytometry MRD surveillance, in context of a negative bone marrow aspirate (MRD &lt;0.01%). Positron emission tomography with 18F-fluorodeoxyglucose revealed diffuse leukemia with innumerable bone and lymph node lesions, interestingly sparing her sacrum, the site of her bone marrow aspirate sampling. Conclusions: We highlight this case as both peripheral blood MRD and 18F-fluorodeoxyglucose positron emission tomography imaging were more sensitive than standard bone marrow aspirate testing in detecting this patient’s post-CAR relapse. Clinical/Biologic Insight: In the multiply relapsed B-ALL setting, where relapse patterns may include patchy medullary and/or EM disease, peripheral blood MRD and/or whole body imaging, may carry increased sensitivity at detecting relapse in patient subsets, as compared with standard bone marrow sampling.
PD-L1 gene amplification and focality: relationship with protein expression
Authors: Denis Leonardo Jardim, Karthikeyan Murugesan, Julia A. Elvin, Richard S. P. Huang, Razelle Kurzrock
Journal: Journal for ImmunoTherapy of Cancer (2023)

PD-L1 (CD274) amplification occurs in a small subset of malignancies and may predict anti-PD-1/PD-L1 immunotherapy responsiveness. We hypothesized that both copy number (CN) and focality of cancer-related PD-L1 amplifications impact protein expression, and, thus, analyzed solid tumors that underwent comprehensive genomic profiling between March 2016 and February 2022 at Foundation Medicine. PD-L1 CN alterations were detected using a comparative genomic hybridization-like method. PD-L1 CN changes were correlated with PD-L1 protein expression (DAKO 22C3 antibody) by immunohistochemistry (IHC). Overall, 60,793 samples were analyzed (most frequent histologies: lung adenocarcinoma (20%), colon adenocarcinoma (12%), lung squamous carcinoma (8%)). Using a definition of CD274 CN ≥ specimen ploidy +4 (6 copies), 1.21% of tumors (738/60,793) were PD-L1 amplified. Focality category distribution was as follows: &lt;0.1 mB (n=18 (2.4%)), ≥0.1 to &lt;4 mB (n=230 (31.1%)), ≥4 to &lt;20 mB (n=310 (42%)), ≥20mB (n=180 (24.4%)). Lower levels of PD-L1 amplification (below specimen ploidy +4) were more frequently non-focal amplifications compared to higher levels. In addition, more focal amplification (&lt;0.1 mB) correlated with higher PD-L1 IHC expression. Median tumor proportion score (TPS) for samples with PD-L1 amplification (ploidy ≥+4) according to focality were 87.5% (&lt;0.1 mB), 80% (≥0.1 to &lt;4 mB), 40% (≥4 to &lt;20 mB), 1% (≥20mB). In specimens with PD-L1 ploidy less than +4, but highly focal (&lt;0.1 mB), the 75th percentile of PD-L1 expression by TPS was 80%. Conversely, non-focal (≥20 mB) PD-L1 amplification (ploidy ≥+4) can present high PD-L1 expression (TPS≥50%), albeit infrequently (0.09% of our cohort). In conclusion, PD-L1 expression measured by IHC is influenced by PD-L1 amplification level and focality. Further correlation between amplification, focality, protein expression and therapeutic outcome for PD-L1 and other targetable genes warrants exploration.
Downregulation of phosphoserine phosphatase potentiates tumor immune environments to enhance immune checkpoint blockade therapy
Authors: Zhi-Peng Peng, Xing-Chen Liu, Yong-Hao Ruan, Da Jiang, Ai-Qi Huang, Wan-Ru Ning, Ze-Zhou Jiang, Limin Zheng, Yan Wu
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Effects of immune checkpoint blockade (ICB) treatment in hepatocellular carcinoma (HCC) are limited. The current study explored the possibility of exploiting tumor metabolic switches to enhance HCC sensitivity to immune therapies. Methods Levels of one-carbon (1C) metabolism and the expression of phosphoserine phosphatase (PSPH), an upstream enzyme of 1C pathway, were evaluated in paired non-tumor and tumor tissues from HCC. Underlying mechanisms mediating the role of PSPH in regulating the infiltration of monocytes/macrophages and CD8 + T lymphocytes were studied through both in vitro and in vivo experiments. Results PSPH was significantly upregulated in tumor tissues of HCC and its levels were positively correlated with disease progression. PSPH knockdown inhibited tumor growth in immunocompetent mice, but not in those with macrophage or T lymphocyte deficiencies, indicating the pro-tumor effects of PSPH were dependent on both immune components. Mechanistically, PSPH facilitated monocytes/macrophages infiltration by inducing the production of C-C motif chemokine 2 (CCL2), while at the same time reduced CD8 + T lymphocytes recruitment through inhibiting the production of C-X-C Motif Chemokine 10 (CXCL10) in tumor necrosis factor alpha (TNF-α)-conditioned cancer cells. Glutathione and S-adenosyl-methionine were partially involved in regulating the production of CCL2 and CXCL10, respectively. sh PSPH (short hairpin RNA) transfection of cancer cells enhanced tumor sensitivity to anti-programmed cell death protein 1 (PD-1) therapy in vivo, and interestingly, metformin could inhibit PSPH expression in cancer cells and mimic the effects of sh PSPH in sensitizing tumors to anti-PD-1 treatment. Conclusions By tilting the immune balance towards a tumor-friendly composition, PSPH might be useful both as a marker in stratifying patients for ICB therapy, and as an attractive therapeutic target in the treatment of human HCC.
Multiomics reveals glutathione metabolism as a driver of bimodality during stem cell aging
Authors: Daniel I. Benjamin, Jamie O. Brett, Pieter Both, Joel S. Benjamin, Heather L. Ishak, Jengmin Kang, Soochi Kim, Mingyu Chung, Marina Arjona, Christopher W. Nutter, Jenna H. Tan, Ananya K. Krishnan, Hunter Dulay, Sharon M. Louie, Antoine de Morree, Daniel K. Nomura, Thomas A. Rando
Journal: Cell Metabolism (2023)
Synergistic therapeutic combination with a CAF inhibitor enhances CAR-NK-mediated cytotoxicity via reduction of CAF-released IL-6
Authors: Young Eun Lee, Ga-Yeon Go, Eun-Young Koh, Han-Na Yoon, Minkoo Seo, Seung-Mo Hong, Ji Hye Jeong, Jin-Chul Kim, Duck Cho, Tae Sung Kim, Song Cheol Kim, Eunsung Jun, Mihue Jang
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) contribute to an impaired functionality of natural killer (NK) cells that have emerged as a promising therapeutic modality. The interaction between CAFs and NK cells within the TME exerts major inhibitory effects on immune responses, indicating CAF-targeted therapies as potential targets for effective NK-mediated cancer killing. Methods To overcome CAF-induced NK dysfunction, we selected an antifibrotic drug, nintedanib, for synergistic therapeutic combination. To evaluate synergistic therapeutic efficacy, we established an in vitro 3D Capan2/patient-derived CAF spheroid model or in vivo mixed Capan2/CAF tumor xenograft model. The molecular mechanism of NK-mediated synergistic therapeutic combination with nintedanib was revealed through in vitro experiments. In vivo therapeutic combination efficacy was subsequently evaluated. Additionally, the expression score of target proteins was measured in patient-derived tumor sections by the immunohistochemical method. Results Nintedanib blocked the platelet-derived growth factor receptor β (PDGFRβ) signaling pathway and diminished the activation and growth of CAFs, markedly reducing CAF-secreted IL-6. Moreover, coadministration of nintedanib improved the mesothelin (MSLN) targeting chimeric antigen receptor-NK-mediated tumor killing abilities in CAF/tumor spheroids or a xenograft model. The synergistic combination resulted in intense NK infiltration in vivo. Nintedanib alone exerted no effects, whereas blockade of IL-6 trans-signaling ameliorated the function of NK cells. The combination of the expression of MSLN and the PDGFRβ + -CAF population area, a potential prognostic/therapeutic marker, was associated with inferior clinical outcomes. Conclusion Our strategy against PDGFRβ + -CAF-containing pancreatic cancer allows improvements in the therapy of pancreatic ductal adenocarcinoma.
Socioeconomic Disparities Affect Outcomes in Early-Stage Esophageal Adenocarcinoma: A SEER Analysis
Authors: Calvin X. Geng, Anuragh R. Gudur, Mark Radlinski, Ross C.D. Buerlein, Daniel S. Strand, Bryan G. Sauer, Vanessa M. Shami, Andrew Y. Wang, Alexander Podboy
Journal: Clinical Gastroenterology and Hepatology (2023)
Alcohol-Associated Liver Disease: Integrated Management With Alcohol Use Disorder
Authors: Juan P. Arab, Giovanni Addolorato, Philippe Mathurin, Mark R. Thursz
Journal: Clinical Gastroenterology and Hepatology (2023)

Alcohol-associated liver disease (ALD) is the most common cause of cirrhosis and liver-related mortality in many regions worldwide. Around 75% of patients with cirrhosis are unaware of their disease until they are referred to the emergency department. An innovative, noninvasive screening approach is required for an earlier diagnosis of liver fibrosis. In patients with ALD the physician is inevitably dealing with 2 major disorders: the liver disease itself and the alcohol use disorder (AUD). Focus only on the liver disease will inevitably lead to failure because transient improvements in liver function are rapidly overturned if the patient returns to alcohol consumption. For this reason, integrated models of care provided by hepatologists and addiction specialists are an effective approach, which are, however, not widely available. There are multiple pharmacologic and non-pharmacologic therapies for AUD. Progress has recently been made in the management of patients with severe AH who have improved survival through better understanding of the concept of response to medical treatment, improved survival prediction, and the advent of early liver transplantation. The emerging concept is that listing for transplantation a patient with severe ALD could lead to adjusting the duration of abstinence according to the severity and evolution of liver dysfunction and the patient's addictive profile.
Neurogenic Аrthropathy, Сhronic Osteomyelitis, Diabetic Foot: Differential X-Ray and MSCT Diagnostics
Authors: G. V. Diachkova, A. S. Sudnitsyn, N. M. Klyushin, A. V. Burtsev, K. A. Diachkov, E. V. Khieva
Journal: Radiology - Practice (2023)

X-ray and MSCT-differential diagnostics between neurogenic arthropathy, diabetic osteoneuroarthropathy (DONAP), complicated by osteomyelitis and chronic osteomyelitis, has not been studied enough. The purpose of the study was to study the MSCT semiotics of various variants of neurogenic arthropathy, DONAP complicated by osteomyelitis and chronic post-traumatic osteomyelitis in order to substantiate etiopathogenetic treatment. In 44 patients with neurogenic arthropathy, DONAP, complicated by osteomyelitis and chronic osteomyelitis, the results of polypositional radiography, MSCT were studied before treatment for the purpose of differential diagnosis. Single center retrospective study. MSCT and x-ray revealed differential diagnostics differences between neurogenic arthropathy, DONAP, complicated by osteomyelitis and chronic osteomyelitis. They are manifested by the localization of destructive processes, characteristic changes in the angles of the foot and a violation of the architectonics of the bones, concomitant changes in blood vessels and soft tissues. Neurogenic arthropathy is characterized by disorganization of the joints, bone resorption, giving the impression of surgical amputation, sharpening of the ends of the metatarsal bones, a symptom of «pestle in a mortar», a violation of the structure of spongy bones. DONAP is manifested by pronounced destructive changes in the midfoot, collapse of the tarsal bones with defects, fragmentation, vascular calcifications (Menckeberg), a «pathological» reference line, an increase in the Meary angle, a decrease in the angle of the calcaneus, and a «rocking foot», increased density of the calcaneus. Chronic osteomyelitis is characterized by an isolated lesion of one or more bones; the presence of a fistulous tract, focal disorders of the trabecular pattern, a decrease in the density of adjacent bones, the presence of isolated foci of sclerosis.
Runx3-overexpression cooperates with ex vivo AKT inhibition to generate receptor-engineered T cells with better persistence, tumor-residency, and antitumor ability
Authors: Jianghui Tang, Jianpeng Sheng, Qi Zhang, Yongtao Ji, Xun Wang, Junlei Zhang, Jiangchao Wu, Jinyuan Song, Xueli Bai, Tingbo Liang
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Solid tumors pose unique roadblocks to treatment with chimeric antigen receptor (CAR) T cells, including limited T-cell persistence, inefficient tumor infiltration, and an immunosuppressive tumor microenvironment. To date, attempts to overcome these roadblocks have been unsatisfactory. Herein, we reported a strategy of combining Runx3 (encoding RUNX family transcription factor 3)-overexpression with ex vivo protein kinase B (AKT) inhibition to generate CAR-T cells with both central memory and tissue-resident memory characteristics to overcome these roadblocks. Methods We generated second-generation murine CAR-T cells expressing a CAR against human carbonic anhydrase 9 together with Runx3 -overexpression and expanded them in the presence of AKTi-1/2, a selective and reversible inhibitor of AKT1/AKT2. We explored the influence of AKT inhibition (AKTi), Runx3 -overexpression, and their combination on CAR-T cell phenotypes using flow cytometry, transcriptome profiling, and mass cytometry. The persistence, tumor-infiltration, and antitumor efficacy of CAR-T cells were evaluated in subcutaneous pancreatic ductal adenocarcinoma (PDAC) tumor models. Results AKTi generated a CD62L+central memory-like CAR-T cell population with enhanced persistence, but promotable cytotoxic potential. Runx 3-overexpression cooperated with AKTi to generate CAR-T cells with both central memory and tissue-resident memory characteristics. Runx3 -overexpression enhanced the potential of CD4+CAR T cells and cooperated with AKTi to inhibit the terminal differentiation of CD8+CAR T cells induced by tonic signaling. While AKTi promoted CAR-T cell central memory phenotype with prominently enhanced expansion ability, Runx3 -overexpression promoted the CAR-T cell tissue-resident memory phenotype and further enhanced persistence, effector function, and tumor-residency. These novel AKTi-generated Runx3 -overexpressing CAR-T cells exhibited robust antitumor activity and responded well to programmed cell death 1 blockade in subcutaneous PDAC tumor models. Conclusions Runx3 -overexpression cooperated with ex vivo AKTi to generate CAR-T cells with both tissue-resident and central memory characteristics, which equipped CAR-T cells with better persistence, cytotoxic potential, and tumor-residency ability to overcome roadblocks in the treatment of solid tumors.
Prospects of the Magnetic Resonance Imaging Method for Assessing the Bioelastic Function of the Aortic Wall
Authors: K. R. Bril’, A. A. Pronkin, T. N. Galyan, М. V. Malakhova, V. Yu. Usov, V. V. Khovrin
Journal: Radiology - Practice (2023)

The distinct growth of cardiovascular diseases (CVD) and aortic diseases in the world requires accurate diagnostic methods for their early prediction. In modern research, more and more attention is paid to biomechanics and numerical models of accurate quantitative calculations. The assessment of aortic pathology using magnetic resonance imaging (MRI) acquires great clinical significance, since it makes it possible to simultaneously assess the anatomical topography and physical properties of the aorta. A broad study of changing biomechanical processes will complement the existing ideas about the basics of aneurysm formation and aortic dissection. MRI is a modern non-invasive method that provides the necessary data to as-sess the physical properties of the wall and directional flows in the aorta.
Erratum: Exposure to Air Pollution during Pre-Hypertension and Subsequent Hypertension, Cardiovascular Disease, and Death: A Trajectory Analysis of the UK Biobank Cohort
Authors: Shiyu Zhang, Zhengmin Min Qian, Lan Chen, Xing Zhao, Miao Cai, Chongjian Wang, Hongtao Zou, Yinglin Wu, Zilong Zhang, Haitao Li, Hualiang Lin
Journal: Environmental Health Perspectives (2023)
Nintedanib (BIBF 1120) plus docetaxel in NSCLC patients progressing after first-line chemotherapy: LUME Lung 1, a randomized, double-blind phase III trial.
Authors: Martin Reck, Rolf Kaiser, Anders Mellemgaard, Jean Yves Douillard, Sergey Orlov, Maciej Jerzy Krzakowski, Joachim Von Pawel, Maya Gottfried, Igor Bondarenko, Meilin Liao, Jose Barrueco, Birgit Gaschler-Markefski, Silvia Novello
Journal: Journal of Clinical Oncology (2013)

LBA8011 Background: Nintedanib (N) inhibits VEGFRs, PDGFRs, and FGFRs. LUME Lung 1 is a placebo (P) controlled phase III trial of N + docetaxel (D) in patients (pts) with locally advanced/metastatic NSCLC progressing after first- line therapy. Methods: Stage IIIB/IV or recurrent NSCLC pts (stratified by histology, ECOG PS, prior bevacizumab, and brain metastases) were randomized to N 200 mg bid + D 75 mg/m 2 q21d (n=655) or P + D (n=659). 1° endpoint was centrally reviewed PFS after 713 events (2 sided stratified log-rank, α=5%, β=10%). Key 2° endpoint of OS was analyzed hierarchically after 1,121 events (2 sided, adjusted α=4.98%, β=20%), first in adenocarcinoma (adeno) pts &lt;9 mo since start of first- line therapy (T&lt;9mo; identified as a prognostic/predictive biomarker [ASCO ‘13]), followed by all adeno pts and then all pts. Predefined sensitivity analyses added sum of longest diameters of target lesions (SLD) to stratification factors in the Cox model. Results: Pt characteristics were balanced between the arms. N + D significantly prolonged PFS vs P + D (HR 0.79; CI: 0.68, 0.92; p=0.0019; median 3.4 vs 2.7 mo) regardless of histology (squamous HR 0.77, p=0.02; adeno HR 0.77, p=0.02). OS was significantly prolonged in all adeno pts (HR 0.83; p=0.0359; median 12.6 vs 10.3 mo) with the greatest improvement seen in T&lt;9mo adeno pts (HR 0.75; p=0.0073; median 10.9 vs 7.9 mo). A trend for improved OS was seen in all pts (HR 0.94; p=0.272; median 10.1 vs 9.1). When adjusted for SLD, a significant OS benefit was seen in all pts (HR 0.88; CI: 0.78, 0.99; p=0.0365). Disease control rates were significantly improved with N + D in all adeno pts (odds ratio [OR] 1.93; p&lt;0.0001), T&lt;9mo adeno pts (OR 2.90; p&lt;0.0001) and all pts (OR 1.68; p&lt;0.0001). The most common AEs were diarrhea (any: 42.3 vs 21.8%; Gr ≥3: 6.6 vs 2.6%) and ALT elevations (any: 28.5 vs 8.4%; Gr ≥3: 7.8 vs 0.9%). Incidence of CTCAE Gr ≥3 AEs was 71.3 vs 64.3%. Withdrawals due to AEs (22.7 vs 21.7%) were similar in both arms, as were Gr ≥3 hypertension, bleeding or thrombosis. Conclusions: N + D significantly improved PFS independent of histology, and prolonged OS for adeno pts. AEs were generally manageable with dose reductions and symptomatic treatment. Clinical trial information: NCT00805194.
Epidemiology of new influenza A (H1N1) virus infection, United Kingdom, April – June 2009
Authors: Collective Health Protection Agency, Health Pr
Journal: Eurosurveillance (2009)

Following the previous report to Eurosurveillance on 14 May 2009, the number of confirmed cases of new influenza A(H1N1) has continued to increase in the United Kingdom. By 31 May, UK surveillance activities had detected a total of 252 confirmed cases. Seventy (28%) were related to travel to the United States and Mexico. There is evidence of spread in households, schools and the community with increases in secondary (n=40), tertiary (n=125) and sporadic (n=13) cases. The new influenza A(H1N1) virus infection continues to cause a mild illness predominately affecting younger age-groups with a low rate of hospitalisation.